The use of caffeine and other alkylxanthines as physiological stimulants is well known. The principle mechanism by which caffeine and other alkylxanthines act as physiological stimulants is by blocking the effects of the ubiquitous neuromodulator adenosine. Daly, "Mechanism of action of caffeine", in Caffeine, Coffee and Health, (S. Garattini, ed), Chapter 4, pp. 97-150 (1993). Adenosine is produced locally in response to increased activity or stress to the system. This feedback mechanism allows the organ to compensate for the stress by decreasing energy demand (depressant activity) and increasing oxygen supply (e.g., by vasodilation). Bruns, Nucleosides & Nucleotides, 10, 931-944 (1991).
Adenosine plays several key physiological roles. In addition to its role in intermediary metabolism, adenosine displays a number of receptor-mediated physiological actions, including dilation of coronary vessels, inhibition of platelet aggregation, and inhibition of lipolysis. Bruns et al., Proc. Nat. Acad. Sci. U.S.A., 77, 5547-5551 (1980). Adenosine receptors, belonging to the superfamily of the G protein-coupled receptors, are generally divided into two major subclasses, A.sub.1 and A.sub.2, on the basis of the differential affinities of a number of adenosine receptor agonists and antagonists for the receptors, their primary structures, and the secondary messenger systems to which they couple. Thus, A.sub.2 receptors, which can be further subdivided into A.sub.2a and A.sub.2b, stimulate adenylate cyclase, whereas A.sub.1 receptors may couple to a variety of secondary messenger systems, including those involved in the inhibition of adenylate cyclase, the inhibition or stimulation of phosphoinositol turnover, the activation of guanylate cyclase, the activation of potassium influx, and the inhibition of calcium influx (van Galen et al., Med. Res. Rev., 12, 423-471 (1992); Jacobson et al., J. Med. Chem., 35, 407-422 (1992)).
Recently, a novel adenosine receptor was identified on the basis of its primary structure and cloned from rat brain (Zhou et al., Proc. Natl. Acad. Sci. U.S.A., 89, 7432-7436 (1992)) and rat testes (Meyerhof et al., FEBS Lett., 284, 155-160 (1991)). The putative transmembrane domains of the novel adenosine receptor, which has been designated the A.sub.3 receptor, show 58% identity with the canine A.sub.1 receptor and 57% with the canine A.sub.2a receptor. Like the A.sub.1 receptor, the A.sub.3 receptor is negatively coupled to adenylate cyclase (Zhou et al.).
The distribution of the A.sub.3 receptor is found primarily in the central nervous system (CNS) (Zhou et al.), brain, testes (Meyerhof et al.), and immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction (Ramkumar et al., J. Biol. Chem., 268, 16887-16890 (1993)). It is believed that A.sub.3 -selective compounds will have utility in the therapeutic and/or prophylactic treatment of cardiac disease, infertility, kidney disease, and CNS disorders.
It is further believed that selective A.sub.3 -adenosine receptor antagonists should serve as cerebroprotective, anti-asthmatic, or anti-inflammatory agents. Beaven et al., Trends Pharmacol. Sci., 15, 13-4 (1994); Jacobson et al., Drugs of the Future, 20, 689-699 (1995); von Lubitz et al., Eur. J. Pharmacol., 275, 23-29 (1995).
Copending U.S. patent applications Ser. No. 08/274,628, filed Jul. 13, 1994, and Ser. No. 08/396,111, filed Feb. 28, 1995, disclose certain A.sub.3 selective agonists, particularly N.sup.6 -benzyladenosine-5'-uronamide and related substituted compounds, xanthine riboside derivatives, pharmaceutical compositions comprising such compounds, and the method of use of such compounds.
The foregoing indicates that there is a need for antagonists for adenosine receptors. The present invention seeks to provide such compounds, as well as methods of using these compounds to selectively block adenosine receptors in mammals, and pharmaceutical compositions comprising such compounds. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.